Endocrine Pancreas PDF

Jason Ryan, MD, MPH Islets of Langerhans Millions of islets found in pancreatic tissue Endocrine portion of pancreas Beta cells: Insulin Most abundant cell type Centrally located Alpha cells: Glucagon Delta cells: Somatostatin Alpha/delta cells: Outer islet...

Jason Ryan, MD, MPH Islets of Langerhans Millions of islets found in pancreatic tissue Endocrine portion of pancreas Beta cells: Insulin Most abundant cell type Centrally located Alpha cells: Glucagon Delta cells: Somatostatin Alpha/delta cells: Outer islet Polarlys/Wikipedia  Protein hormone Synthesized by beta cells Synthesized as preproinsulin Made by ribosomes of rough endoplasmic reticulum Preproinsulin cleaved to proinsulin Transported to Golgi apparatus Packaged into secretory granules Proinsulin cleaved to insulin and C-peptide in granules  C-peptide Alpha chain Beta chain α chain Disulfide bridges C-peptide “Connecting” peptide Long half-life β chain Zapyon/Wikipedia Indicator insulin production  GLUT-2 and Glucokinase Both in liver/pancreas Glucokinase Prisonblues /Wikipedia  Produced in response to: glucose, amino acids Glucose Amino Acid Wikipedia/Public Domain  Production inhibited by epinephrine Beta-2 receptors: ↑ insulin Alpha-2 receptors: ↓ insulin release Alpha effect is dominant effect in pancreas Fight or flight response  ↑ plasma glucose  Beta cell enzyme Glucose 1 step of glycolysis st ATP Found in liver and pancreas Induced by insulin ADP Insulin promotes transcription Glucose-6-phosphate High Km (rate varies with glucose) High Vm (can convert lots of glucose)  Bidirectional glucose transporter Found in liver, kidney, beta cells Liver, kidney: Gluconeogenesis Beta cells: Glucose in/out based on plasma levels Also found in intestine, other tissues Key Points Glucose into beta cells via GLUT-2 Glucose  G-6P via glucokinase ATP produced  Closure of K+ channels Depolarization Voltage-gated calcium channels open Calcium  insulin release from vesicles  Tetramer α Insulin Two α units Two β units Disulfide bonds Step 1: Insulin Binding Activates “Tyrosine Kinase” domains within receptor complex “Tyrosine Kinase Receptor”  Tyrosine Ty Ty Ty Ty P P Step 2: Tyrosine Phosphorylation Receptor phosphorylates itself “Autophosphorylation” IRS-1 Ty Ty P P Step 3: Binds Substrates IRS: Insulin receptor substrate IRS-1, IRS-2, etc. Mediate downstream effects  IRS-1 Ty Ty IRS-1 P P Step 4: Downstream Signaling Option 1: PIK3 Pathway Option 2: RAS/MAP Kinase Pathway Phosphatidylinositol 3–kinase Pathway Intracellular lipid kinases Phosphorylate 3’-hydroxyl group of phospholipids Forms PIP3 from PIP2 Phosphatidylinositol Phosphatidylinositol 3–kinase Pathway Catalyzes many intracellular processes Glycogen formation Fatty acid synthesis GLUT-4 glucose transporter [Glucose] GLUT 4 [Glucose]  Stored in vesicles in cells, especially muscle Insulin  PIK3 pathway  GLUT-4 Activation Major mechanism for increased glucose uptake Important muscle/fat Insulin exposure  GLUT-4 on surface [Glucose] GLUT 4 [Glucose]  Insulin receptor can activate RAS G protein RAS can activate many growth pathways Raf MEK (mitogen-activated extracellular kinase) MAP (mitogen-activated protein) Modify cell growth and gene expression Key Points Tetramer of α/β subunits with disulfide bridges α: extracellular β: transmembrane Insulin binding  tyrosine kinase activity Autophosphorylation of tyrosine residues PIK3 Pathway  GLUT-4 glucose transporter RAS/MAP Kinase Pathway: growth/gene transcription  Muscle and fat Use GLUT-4 for glucose uptake Depend on insulin (no insulin = no GLUT-4) [Glucose] GLUT 4 [Glucose]  Brain and RBCs Use GLUT-1 for glucose uptake Not dependent on insulin Takes up glucose when available RBCs: No mitochondria (depend on glycolysis) Brain: No fatty acid metabolism (glucose/ketones) Liver, kidney, intestines Also insulin independent (GLUT-2) Other organs: nerves, lens  Glucose uptake (skeletal muscle, adipose tissue) Glycogen synthesis Activates glycogen synthase Inhibits glycogen phosphorylase Inhibits gluconeogenesis ↑ Fructose-2,6-bisphosphate levels Inhibit Fructose 1,6 bisphosphatase 1  Fatty acid synthesis Activates acetyl-CoA carboxylase Inhibits hormone sensitive lipase Protein synthesis Stimulates entry of amino acids into cells  protein synthesis Important for muscle growth Key side effect insulin therapy: weight gain  Removes fatty acids from TAG in adipocytes Inhibited by insulin Activated by glucagon and epinephrine Fatty Acid Hormone Sensitive Lipase Triacylglycerol Liver Glycerol  Na+ retention Increases Na+ resorption in the nephron Lowers potassium Enhanced activity of Na-K-ATPase pump in skeletal muscle Insulin plus glucose used in treatment of hyperkalemia Inhibits glucagon release  Protein hormone Single polypeptide chain Synthesized by alpha cells Opposes actions of insulin Main stimulus release: low plasma glucose  Increases liver (not muscle) glycogen breakdown Raises blood glucose level Increases gluconeogenesis  Increases amino acid uptake in liver More carbon skeletons for glucose via gluconeogenesis Plasma amino acid levels fall Activates lipolysis via hormone sensitive lipase  G-protein receptor G-protein Receptor Activates adenylyl cyclase Increases cAMP Activates protein kinase A (PKA) G-protein 2nd Messenger Image: “Activation cycle of G-proteins by G-protein-coupled receptors” by Sven Jähnich  Glucagon receptors mostly in liver Many activated processes occur in liver Breakdown of glycogen to raise plasma glucose Gluconeogenesis Most other tissues have lower density than liver Not found in skeletal muscle Watanabe M, et al. Histologic distribution of insulin and glucagon receptors. Brazilian Journal of Medical and Biological Research (1998) 31: 243-256  Unconscious patient with hypoglycemia Treatment: #1: IV dextrose #2: Intramuscular glucagon Useful when IV access cannot be established Raises plasma glucose level  Causes bradycardia and hypotension Drug of choice: Glucagon Activates adenylyl cyclase Different site from beta-adrenergic agents Raises cAMP  ↑ myocyte calcium Same mechanism as beta stimulation (via Gs proteins)  Rare, pancreatic islet-cell tumor Occurs in adults (median age ~50 years) Key feature: fasting hypoglycemia Insulin levels remain elevated when fasting “Neuroglycopenic symptoms” Confusion, odd behavior Sympathetic activation from low glucose Palpitations, diaphoresis, tremor  Diagnosis: fasting insulin level Also elevated C-peptide Proinsulin Need to exclude exogenous insulin administration  Differential diagnosis Exogenous insulin Oral hypoglycemics (sulfonylureas  ↑ insulin) Insulinoma  Rare pancreatic tumors Excess glucagon secretion Leads to glucose intolerance Elevated fasting glucose levels Rare to develop DKA (insulin function intact)  Weight loss Liver gluconeogenesis Consumption of proteins/amino acids  Necrolytic migratory erythema Red, blistering rash Itchy, painful Fluctuates in severity Genitals, buttocks, groin Key clinical scenario: new diabetes and rash  Diagnosis: ↑ plasma glucagon level Treatment: somatostatin analogs (octreotide) Inhibit glucagon secretion Improves symptoms  Multiple endocrine neoplasia Rare inherited disorders Numerous endocrine tumors MEN Type 1: Insulinomas/glucagonomas 3 P’s: Pituitary, Parathyroid, and Pancreas Mutations of MEN1 tumor suppressor gene Jason Ryan, MD, MPH  Chronic disorder of elevated blood glucose levels Caused by: Insufficient insulin Insufficient response to insulin (“insulin resistance”) Both  Often asymptomatic “Silent killer” Often no symptoms until complications develop Basis for screening Classic hyperglycemia symptoms Polyuria (osmotic diuresis from glucose) Polydipsia (thirst to replace lost fluids)  Diabetes Mellitus Mellitus = sweet Common disorder of blood glucose Diabetes insipidus Insipid = lacking flavor Rare disorder of low ADH activity Both can cause polyuria, polydipsia Completely different mechanisms  Symptoms Symptoms plus glucose >200mg/dl = diabetes Asymptomatic Fasting blood glucose level (no food for 8 hours)  Small fraction of hemoglobin is “glycated” Glucose combines with alpha/beta chains Subfraction HbA1c used in diabetes Non-enzymatic glycation of beta-chains Occurs at amino-terminal valines NH2 Glucose  Reflects average glucose over past 3 months Normal < 5.7% Pre-diabetes: 5.7 to 6.4% Diabetes: >=6.5% Sometimes used for diagnosis Important for monitoring therapy Higher value = worse control of blood sugar  Oral glucose load administered Plasma glucose measured 1-3 hours later High glucose indicates diabetes Often used to screen for gestational diabetes Some insulin resistance normal in pregnancy Need to study response to glucose load for diagnosis  Autoimmune disorder Type IV hypersensitivity reaction T-cell mediated destruction of beta cells Inflammation of islets Lymphocytes on biopsy (“Insulitis”) Decreased number of beta cells Loss of insulin Associated with HLA-DR3 and HLA-DR4 Autoantibodies may be present Islet-cell antibodies Insulin antibodies  Mostly a childhood disorder Bimodal distribution Peak at 4-6 years Wikipedia/Public Domain 2nd peak 10 to 14 years of age Often presents with symptomatic hyperglycemia Polyuria Polydipsia Glucose in urine Treatment: Insulin DKA Life-threatening complication of diabetes More common type 1 Common initial presentation type 1 Often precipitated by infection/trauma Can occur when type 1 diabetic skips insulin therapy DKA ↓ Insulin ↑ Glucagon ↑ Epinephrine Polyuria ↑ Glucose ↑ Lipolysis Dehydration Fruity ↑ Ketones Breath Urine Ketones Urine Glucose Acidosis Abd Pain ↓ GI (AG) Motility Nausea Vomiting ↓ Phosphate ↑ plasma K+ Clinical Presentation Abdominal pain/nausea/vomiting Dehydration Hyperglycemia Hyperkalemia Elevated plasma/urine ketones Glucose in urine Anion gap metabolic acidosis Kussmaul breathing: deep, labored breathing Hyperventilation to blow off CO2 and raise pH Fruity smell on breath DKA Low insulin/high epinephrine High fatty acid utilization Oxaloacetate depleted  TCA cycle stalls ↑ acetyl-CoA Ketone production Fatty Acids Acetyl-CoA Ketones Glucose NADH Oxaloacetate Citrate Malate  Risk of hypophosphatemia Acidosis  shifts phosphate to extracellular fluid Phosphaturia caused by osmotic diuresis Loss of ATP Muscle weakness (respiratory failure) Heart failure (↓ contractility) Clinical Presentation Arrhythmias (hyperkalemia) Cerebral edema Mechanism poorly understood Common cause of death in children with DKA Pixabay/Public Domain _DJ_/Wikipedia  Fungal infection Caused by Rhizopus sp. and Mucor sp. Classically starts in sinuses Spreads to adjacent structures Thrives in high glucose, ketoacidosis conditions Classic complication of DKA Patient with DKA Fever, headache, eye pain Image courtesy of Yale Rose/Flickr Treatment Insulin Lowers blood glucose levels Shifts potassium into cells IV fluids Treats dehydration Harmid/Wikipedia BruceBlaus/Wikipedia Treatment Careful monitoring potassium Total body potassium is low despite hyperkalemia Insulin shifts into cells  can lead to hypokalemia Usually need to administer potassium Careful monitoring glucose Continue insulin until acidosis resolves Often add glucose while insulin infusion continues  Insulin resistance Muscle, adipose tissue, liver Reduced response to insulin  hyperglycemia Pancreas responds with ↑ insulin Eventually pancreas can fail  ↓ insulin Risk Factors Most common form of diabetes Common in adults Prevalence is rising Also becoming more common among children Risk Factors Major risk factor: Obesity Central or abdominal obesity carries greatest risk Intra-abdominal (visceral) fat > subcutaneous fat Visceral fat breakdown less inhibited by insulin More lipolysis  more free fatty acids Decreased glucose transport into cells “Apple shape” worse than “pear shape” Apple shape due to increased visceral adipose tissue More subcutaneous adipose tissue in pear shape Weight loss improves glucose levels Risk Factors Major risk factor: Obesity Central or abdominal obesity carries greatest risk Intra-abdominal (visceral) fat > subcutaneous fat Visceral fat breakdown less inhibited by insulin More lipolysis  more free fatty acids Decreased glucose transport into cells “Apple shape” worse than “pear shape” Apple shape due to increased visceral adipose tissue More subcutaneous adipose tissue in pear shape Weight loss improves glucose levels Risk Factors Family history Strong genetic component (more than type I) Any irst degree relative with T2DM: ↑ 2-3x risk Insulin Resistance Mechanism Reason for insulin resistance not known Many data suggest insulin receptor abnormalities Fatty acids may activate serine-threonine kinases Phosphorylate amino acids on beta chain of insulin receptors Inhibiting tyrosine phosphorylation ↑ TNF-α may be synthesized by adipocytes TNF-α can activate serine-threonine kinases Serine Threonine Histology Classic finding is amyloid in pancreatic islets Amylin peptide normally made by beta cells Precise function not known Packaged and secreted with insulin Pramlintide: amylin analog used for diabetes treatment Accumulates in islets in patients with type 2 diabetes Hyperglycemic Hyperosmolar Syndrome Life-threatening complication of diabetes More common type 2 High glucose  diuresis Markedly elevated glucose (can be >1000) Severe dehydration Different from DKA Few or no ketone bodies (insulin present) Usually no acidosis Very high serum osmolarity  CNS dysfunction Hyperglycemic Hyperosmolar Syndrome Polyuria, polydipsia Dehydration Mental status changes Confusion Coma Treatment similar to DKA (insulin, IVF)  Hyperpigmented plaques on skin Intertriginous sites (folds) Classically neck and axillae Associated with insulin resistance Often seen obesity, diabetes Rarely associated with malignancy Gastric adenocarcinoma most common Madhero88/Dermnet.com  Chronic hyperglycemia  complications Cardiac disease Renal failure Neuropathy Blindness Two key underlying mechanisms Non-enzymatic glycation Sorbitol accumulation  Glucose added to amino groups on proteins No enzyme required Driven by high glucose levels Leads to crosslinked proteins “Advanced glycosylation end products” (AGEs) Diabetic Macroangiopathy AGEs trap LDL in large vessels  atherosclerosis Coronary artery disease Angina, myocardial infarction Stroke/TIA Peripheral vascular disease Claudication Arterial ulcers Poor wound healing Gangrene BruceBlaus/Wikipedia Diabetic Microangiopathy AGEs  damage to glomerulus and arterioles Leads to end stage kidney disease in many diabetics Diabetic Microangiopathy AGEs Basement Efferent Afferent Membrane Arteriole Arteriole Thickening Glomerulosclerosis Hyperfiltration ↓ RBF Renal Failure Albuminuria  Hyaline arteriosclerosis Thickening of arterioles Also seen in HTN Can result from AGEs Crosslinking of collagen Nephron/Wikipedia Commonly occurs in kidneys of diabetics Can involve afferent AND efferent arteriole Afferent arteriole: Ischemia Efferent arteriole: Hyperfiltration Efferent arteriosclerosis rarely seen except in diabetes  Annual screening for albumin in urine Evidence of protein is indication for ACE-inhibitor ACEi shown to reduce progression to ESRD Potential mechanism is dilation of efferent arteriole Reduction in hyperfiltration  AGEs  diffuse basement membrane thickening Visible on electron microscopy Can lead to mesangial proliferation in glomeruli End result is glomerulosclerosis  Diffuse glomerulosclerosis Deposits of proteins (collagen IV) Diffusely on basement membranes of glomeruli capillary loops Mesangial cell proliferation Also occurs with aging and hypertension If severe  nephrotic syndrome Nodular glomerulosclerosis Nodules form in periphery of glomerulus in mesangium Rarely occurs except in diabetes Can lead to fibrosis/scarring of entire kidney  Hallmark of nodular sclerosis of diabetes Pathognomonic of diabetic kidney disease bilalbanday Polyol Pathway NADPH NADP+ NAD+ NADH Glucose Sorbitol Fructose Aldose Sorbitol Reductase Dehydrogenase  Little activity at physiologic glucose levels Chronic hyperglycemia can lead to ↑sorbitol Sorbitol is osmotic agent Draws in fluid  osmotic damage Likely involved in many diabetic complications Cataracts Neuropathy  Sorbitol accumulates in lens ↑ osmolarity Fluid into lens Rakesh Ahuja, MD/Wikipedia Opacification over time  Sorbitol can accumulate in Schwann cells Myelinating cells of peripheral nerves Osmotic damage  neuropathy  Classically causes “stocking-glove” sensory loss Longest axons affected most Often feet/legs Worse distally; better proximally Loss of vibration sense, proprioception Impairment of pain, light touch, temperature Autonomic neuropathy Postural hypotension Delayed gastric emptying  Neuropathy + ischemia can lead to: Ulcers Infection Amputation Made worse by poor wound healing from PVD Prevention: Regular foot exams Ulcer treatment: Wound management Sometimes antibiotics Hyperbaric oxygen chamber DrGnu/Wikipedia  Can cause blindness among diabetics Multiple factors likely involved: Capillary basement membrane thickening (AGEs) Hyaline arteriosclerosis Pericyte degeneration Cells that wrap capillaries Evidence of sorbitol accumulation Microaneurysms Rupture  hemorrhage Annual screening for prevention Findings Microaneurysms, Hemorrhages Loss of pericytes Exudates Leakage proteins, lipids Cotton-wool spots "Blausen gallery 2014“ Nerve infarctions Wikiversity Journal of Medicine. Occlusion of precapillary arterioles Vessel proliferation (“proliferative retinopathy”) Retinal ischemia  new vessel growth “Neovascularization”  Non-enzymatic Sorbitol Glycation Accumulation Atherosclerosis Diabetic Retinopathy Neuropathy Kidney Disease Cataracts CAD Stroke PVD Jason Ryan, MD, MPH  Type 1 diabetes treated mainly with insulin Type 2 diabetes: oral or SQ drugs +/- insulin Initial stages: Oral and/or SQ drugs Advanced disease: Insulin  Many different types available for diabetes therapy All vary by time to peak and duration of action Also vary by peak effect Rapid Regular NPH Detemir Glargine Acting Insulin Insulin Insulin Fast Peak Slow Peak Short Duration Long Duration  Insulin forms hexamers in the body Six insulin molecules linked Stable structure Isaac Yonemoto /Wikipedia Insulin usually administered subcutaneously Activity related to speed of absorption Insulin hexamers  slower onset of action Insulin monomers  faster onset of action Lispro, Aspart, and Glulisine Modified human insulin Contain insulin with modified amino acids Reduced hexamer/polymer formation Rapid absorption, faster action, shorter duration Onset: 15 minutes Peak: 1 hour Duration: 2 to 4 hours Often used pre-meal Rapid 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Administration  Synthetic analog of human insulin Made by recombinant DNA techniques Onset: 30 minutes Peak: 2 to 3 hours Duration: 3 to 6 hours Rapid Regular 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Administration  Commonly used in hospitalized patients Blood sugar elevations common with infection/surgery Sliding scale dose given based on finger stick blood sugar “Regular insulin sliding scale” Only type of insulin that is given IV IV regular insulin used in DKA/HHS Used to treat hyperkalemia Given IV with glucose to prevent hypoglycemia Neutral Protamine Hagedorn Regular insulin combined with neutral protamine Slows absorption Peak: 4-8 hours Duration: 12-16 hours Rapid Regular NPH 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Administration  Insulin with modified amino acid structure Soluble in acidic solution for dosing Precipitates at body pH after SQ injection Insulin molecules slowly dissolve from crystals Low, continuous level of insulin Onset: 1–1.5 hours Duration: 11–24 hours Often given once daily Rapid Regular NPH Glargine 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Administration  Insulin with fatty acid side chain added Slow rate of absorption Aggregation in subcutaneous tissue Also binds reversibly to albumin Onset:1–2 hours Duration: > 12 hours Usually given once or twice daily May cause less weight gain Rapid Regular NPH Detemir Glargine 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Administration  Rapid-acting Pre-meal Regular Sliding scale IV for treatment of DKA, hyperkalemia NPH, Glargine, Detemir Often given as background therapy  Do not contain human insulin molecules Modified insulin structure Rapid acting, Detemir, Glargine Regular insulin, NPH Contain human insulin molecules Regular: made by recombinant techniques NPH: Regular added to neutral protamine to slow absorption  Major side effect of all insulin regimens Tremor, palpitations, sweating, anxiety If severe: seizure, coma Always check blood sugar in unconscious patients Dosages, frequency adjusted to avoid low glucose  Occurs in most patients on insulin Insulin promotes fatty acid and protein synthesis Wikipedia/Public Domain